Staging

In 2014, the International Conference on Malignant Lymphomas (a multidisciplinary team of researchers representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan, and Australasia) published guidelines for the evaluation, staging, and response assessment of patients with malignant lymphomas. This staging system is known as the Lugano Modification of the Ann Arbor staging system.
[14] In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system.
[15]

Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning

PET-CT is preferred for determining splenic involvement, with cutoff for splenomegaly of more than 13 cm

Bone marrow biopsy is usually not required if the PET-CT scan indicates bone or marrow involvement but if the scan is negative, a bone marrow biopsy is indicated to identify involvement by discordant histology, if clinically relevant

Liver size is not a reliable measure; liver involvement is suggested by diffusely increased or focal uptake, with or without focal or disseminated nodules

Prior Ann Arbor staging divided patients according to absence (A) or presence (B) of disease-related symptoms (B symptoms include weight loss >10%, fever, drenching night sweats); these are not required in NHL staging since they are not prognostic

In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification, as shown in Table 1, below
[15, 14] :

Stage I or II by nodal extent with limited contiguous extranodal involvement

II bulky*

Multiple lymph node groups on same side of diaphragm with “bulky disease”

N/A

III

Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement

N/A

IV

Multiple noncontiguous extranodal sites

N/A

*Stage II bulky disease is considered limited or advanced; this distinction is made on the basis of histology and a number of prognostic factors.

Suffixes A and B are not required. X for bulky disease replaced with documenting of largest tumor diameter. Definition of “bulky” disease varies, depending on lymphoma histology.

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Risk Stratification

The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive non-Hodgkin lymphoma (NHL), also appears to be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen.
[8] Separate indices have been developed for follicular and mantle cell lymphoma.
[9, 10, 11]

Each factor is worth 1 point. Based on the IPI score, patients can be categorized as follows
[8] :

Low risk (0-1 point)

Low-intermediate risk (2 points)

High-intermediate risk (3 points)

High risk (4-5 points)

With this model, relapse-free and overall survival rates at 5 years are as follows:

0-1 risk factors - 75%

2-3 risk factors - 50%

4-5 risk factors - 25%

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Follicular Lymphoma

World Health Organization Classification

In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes.
[3, 17]

National Comprehensive Cancer Network (NCCN) guidelines note that that grade 3B is commonly treated as diffuse large B-cell lymphoma (DLBCL), whereas opinion is divided on whether to treat grade 3A as FL or DLBCL. FL of any grade that is found to contain an area of DLBCL should be managed as a DLBCL.
[18]

Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.
[3]

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL
[15] :

The NCCN recommends both the GELF criteria and the 2004 Follicular Lymphoma International Prognostic Index (FLIPI) for risk stratification. The FLIPI includes the following risk factors
[10] :

Age >60 y

Ann Arbor Stage III-IV

Lactate dehydrogenase (LDH) level above the upper limit of normal

Hemoglobin level <12 g/dL

Five or more nodal sites of disease

For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows
[10] :

Low risk (0 or 1 point)

Intermediate risk (2 points)

High risk (≥3 points)

In 2009, the International Follicular Lymphoma Prognostic Factor Project published an updated score, FLIPI2. The FLIPI2 includes the following risk factors (as with FLIPI1, each factor is worth 1 point)
[9] :

Age >60y

β2-microglobulin (B2M) above the upper limit of normal

Bone marrow involvement

Hemoglobin level <12 g/dL

Longest diameter of the largest involved node >6 cm

Based on the FLIPI2 score, patients can be categorized as low, intermediate, or high risk.
[9]

Obinutuzumab maintenance for rituximab-refractory disease (1 g every 8 wk for total of 12 doses)

High-dose therapy with autologous stem cell rescue

Allogeneic stem cell transplant for highly selected patients

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Marginal Zone Lymphomas of MALT Type

Mucosa-associated lymphoid tissue (MALT) lymphomas are usually localized and are most often observed in the stomach, lung, salivary gland, thyroid, orbit, conjunctiva, and lacrimal gland. An association of MALT lymphomas with autoimmune disease is well known.

The development of gastric MALT lymphomas has been attributed to antigenic stimulation associated with chronic Helicobacter pylori gastritis. Indeed, both the NCCN and ESMO guidelines recommend antibiotic eradication of H pylori as first-line treatment for H pylori–positive patients, including t(11;18)-positive patients. After eradication of H pylori, t(11;18) patients have a <5% response rate to the tumor. They will require involved-site radiation therapy (ISRT) or rituximab. In H pylori –negative patients, involved-site radiation therapy (ISRT), 30 Gy, is the preferred treatment option. Rituximab is an option if radiation therapy is contraindicated.
[18]

For non-gastric MALT lymphomas, radiotherapy is preferred but surgery is also an appropriate treatment (and in most cases is required to make the diagnosis). Further treatment may not be needed. When the tumor is incompletely excised, radiotherapy should be considered. In the minority of patients presenting with a more widespread disease, systemic chemotherapy is effective. The majority of stage III-IV MALT lymphomas respond to treatment similar to that for follicular lymphoma.
[18]

Therapy for gastric MALToma

European Society for Medical Oncology (ESMO) guidelines for treatment of gastric marginal zone lymphoma of the MALT type include the following recommendations
[20] :

Helicobacter pylori eradication therapy must be given to all gastric MALT lymphomas, independently of stage, and may be considered for
H pylori–negative cases

If no signs of lymphoma regression are seen at a repeat endoscopy assessment 2 to 3 months after antibiotic treatment, radiation and systemic oncological therapies should be used, depending on the stage of disease

Radiotherapy might be the preferred option for localized disease (eg, 24–30 Gy to the stomach and perigastric nodes given in 3 to 4 weeks)

Chemoimmunotherapy is preferred in cases of histological transformation or contraindications to radiotherapy; patients with
t(11;18) will most probably be unresponsive to alkylating agents as a sole treatment

No accepted standard chemotherapy has been established, but oral alkylating agents (either cyclophosphamide or chlorambucil) or purine nucleoside analogues (fludarabine, cladribine) and the combination of rituximab and bendamustine have shown benefit

No data support a rituximab maintenance strategy.

Aggressive anthracycline-containing regimens are not usually necessary and should be reserved for the few patients with a very aggressive clinical course or histological transformation

Surgery has no role in initial treatment

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Mantle Cell Lymphoma

Diagnosis

Mantle cell lymphoma (MCL) is diagnosed in accordance with the World Health Organization criteria for hematological neoplasms and detection of Cyclin D1 expression or the t(11;14) translocation along with mature B-cell proliferation.
[20] The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL
[18] :

Based on the MIPI score, patients can be categorized as follows
[11] :

Low risk (0-3 points)

Intermediate risk (4-5 points)

High risk (≥6 points)

In addition, both the NCCN and ESMO recommend assaying Ki-67 proliferative antigen to evaluate cell proliferation. Low Ki-67 (<30%) is associated with a more favorable prognosis; however, it is not used to guide treatment decisions.
[15, 21]

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows
[15, 21]

Chemotherapy followed by involved-site radiation therapy (ISRT), 30-36 Gy, is the preferred treatment option for limited stage I or II (non-bulky) disease, although this presentation is rare

Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.

In elderly fit patients, less-aggressive induction regimens followed by rituximab maintenance is recommended by both NCCN and ESMO

For elderly patients who are not candidates for any of the above chemotherapy regimens, palliative chemotherapy should be considered, using milder chemo-immunotherapy regimens (eg, chlorambucil plus rituximab, bendamustine plus rituximab)

For relapsed or refractory disease, recommendations include high-dose therapy with autologous stem cell rescue and second-line agents; allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation

See second-line therapy for DLBCL (BCEL-C 2 of 4) without regard to transplantability

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Diffuse Large B-Cell Lymphoma

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of diffuse large B-cell lymphoma (DLBCL)
[15] :

IHC should include adequate markers to differentiate the two subtypes of DLBCL: activated B-cell type (ABC) and germinal center B-cell type (GCB). The subtypes are genetically different diseases, and survival in patients with the ABC subtype is worse than in those with GCB.
[22]

Risk stratification

The NCCN and the European Society for Medical Oncology (ESMO) recommend use of the International prognostic index (IPI) for all patients. Age-adjusted International Prognostic Index (aa-IPI) should be used for risk stratification of patients aged 60 years and younger.
[15, 23]

The IPI includes the following risk factors:

Age >60 years

Elevated serum lactate dehydrogenase (LDH) level

Eastern Cooperative Oncology Group (ECOG) performance status ≥2

Stage III or IV disease

Extranodal involvement >1 site

Each risk factor is worth 1 point. On the basis of the IPI score, patients can be categorized as follows:

Low risk (0-1 point)

Low-intermediate risk (2 points)

High-intermediate risk (3 points)

High risk (4-5 points)

The aa-IPI includes the following risk factors (1 point is allotted for each factor)
[8] :

Elevated LDH level

Stage III or IV disease

ECOG performance status ≥2

Based on the aa-IPI score, patients can be categorized as follows
[8] :

Follow-up

A PET-CT scan should be performed to confirm complete remission (CR). Patients in CR should receive clinical follow-up with a history and physical examination and laboratory studies (eg, complete blood cell count, comprehensive metabolic panel, lactate dehydrogenase level) every 3-6 months for 5 years and then yearly or as clinically indicated. Imaging studies (CT scan) should be performed no more often than every 6 mo for 2 years after the completion of treatment, and then only as clinically indicated.
[18]

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Burkitt Lymphoma

Classification

The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL)3:

Endemic (eBL) – The most common form of childhood malignancy in equatorial Africa, associated with Epstein-Barr virus (EBV) infection

Sporadic (sBL) – The majority of cases are in the United States and Europe; up to 30% are associated with EBV

• RICE (rituximab, ifosfamide, carboplatin, etoposide); intrathecal methotrexate if have not received previously

• RIVAC (rituximab, ifosfamide, cytarabine, etoposide); intrathecal methotrexate if have not received previously

• RGDP (rituximab, gemcitabine, dexamethasone, cisplatin)

• High-dose cytarabine + rituximab

Content.

Follow-up

The NCCN recommends follow up every 2-3 months for the first year after complete response, then every 3 months for the next year, and every 6 months thereafter. Relapse is rare after 2 years.12

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Primary Cutaneous B-Cell Lymphomas

In addition to the National Comprehensive Cancer Network (NCCN), the European Organization for Research and Treatment of Cancer (EORTC) and the International Society for Cutaneous Lymphoma (ISCL) published guidelines for the management of primary cutaneous B-cell lymphomas (CBCL).
[24]

Classification

The NCCN and EORTC/ISCL guidelines recommend use of the WHO-EORTC classification for cutaneous B-cell lymphomas (CBCL), which distinguishes the following three main types
[25] :

Primary cutaneous marginal zone lymphoma (PC-MZL)

Primary cutaneous follicle center cell lymphoma (PC-FCL)

Primary cutaneous diffuse large B-cell, leg type (PC-DLBCL, LT)

Of note, a germinal (or follicle) center phenotype and large cells in a skin lesion is not equivalent to diffuse large B-cell lymphoma (DLBCL) but is consistent with primary cutaneous germinal/follicle center lymphoma.

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of CBCL
[15] :

Assessment of IgM and IgD expression to distinguish between PC-FCL and PC-DLBCL, leg type

Fluorescence in situ hybridization (FISH) or cytogenetics for detection of
t(14;18)

Bone marrow biopsy in PC-FCL, optional for PC-MZL

Staging

The 2007 TNM classification system of the ISCL/EORTC is used for staging, as shown in Table 3, below.
[26]

Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma (Open Table in a new window)

Tumor

Involvement

Node

Involvement

Metastatic Spread

Involvement

T1

Solitary skin involvement

T1a: ≤5 cm diameter

T1b: >5 cm diameter

N0

No lymph node involvement

M0

No evidence of extracutaneous non-lymph node disease

T2

Multiple lesions limited to one body region or two contiguous body regions

T2a: all-disease in a <15-cm diameter

T2b: all-disease in a >15- and <30-cm diameter

T2c: all-disease in a >30-cm diameter

N1

Involvement of one peripheral lymph node region

M1

Evidence of extracutaneous non-lymph node disease

T3

Generalized skin involvement

T3a: multiple lesions involving two noncontiguous body regions

T3b: multiple lesions involving three body regions

N2

Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement

N3

Central lymph nodes involvement

Treatment

PC-FCL and PC-MZL

Both the NCCN and EORTC/ISCL guidelines recommend local radiation therapy or excision for T1-2 PC-FCL and PC-MZL.
[15, 24] The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options.
[15]

For T3 disease, the NCCN recommends radiation therapy; chlorambucil; or cyclophosphamide, vincristine, and prednisone (CVP) with or without rituximab. Extracutaneous disease should be managed using the treatment guidelines for follicular lymphoma.
[15]

EORTC/ISCL guidelines recommend systemic rituximab as the first choice of treatment for patients with extensive skin lesions. Combination chemotherapy (eg, R-COP, R-CHOP) should be considered only in exceptional cases, such as in patients with progressive disease not responding to rituximab or patients developing extracutaneous disease.
[24]

PC-DBCL, LT

Both guidelines caution that radiation therapy is less effective in PC-DBCL, LT. R-CHOP with local radiation therapy is recommended as first line of treatment for all stages of DBCL, LT.
[15, 24] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed.
[24] .

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Sara J Grethlein, MD, and Uzma Athar, MD, to the development and writing of the source article.